Could
something as simple and inexpensive as a vitamin pill boost resistance
to Mycobacterium tuberculosis, one
of the most formidable and deadliest
pathogens on Earth? It's an idea not to be dismissed, say immunologists
from the University of California, Los Angeles (UCLA) and the Harvard
School of Public Health (HSPH). In the March 6 issue of Science, they
have published a study that may help explain why people of African descent--and
perhaps also others of color, including Asians--have long been known
to be more vulnerable to TB than whites.

The possible key to their susceptibility?
A deficit in vitamin D.

The tubercle bacillus infects about one
in three people worldwide, according to the World Health Organization
(WHO).
While in most people
the microbe
either lies dormant for years or is killed quickly by first-line
immune defenses, it also causes nearly 9 million cases of active infection
and more than 2 million deaths, according to WHO estimates. People
of African
descent have been known to develop active TB far more readily than
whites do, and their disease, if untreated, is also generally more
severe. In
the United States, according to the Centers for Disease Control and
Prevention, TB case rates for African Americans are about eight times
higher than
they are for whites.

The new study found that the body's "innate" immune
response to infection--a swift, first-line defense against a
variety of pathogens by immune scavenger cells called macrophages--is
critically dependent on vitamin D. The body makes vitamin D when
the sun's
ultraviolet rays hit the skin. But in dark-complexioned populations,
the skin pigment, melanin, absorbs those rays, lowering vitamin D
levels in the blood.

TB
IN BLACK AND WHITE

Of the world's
22 highest-burden TB countries, nine are in Africa, according to
the World Health
Organization
(WHO). They are:
Democratic Republic of Congo, Ethiopia, Kenya, Mozambique, Nigeria,
South Africa, Uganda, United Republic of Tanzania, and Zimbabwe.
These countries face huge challenges related to the HIV/AIDS epidemic,
which greatly weakens the immune system and heightens the risk of
infection and death caused by TB.

The largest
number of new TB cases in 2004 occurred in WHO's
11-country South-East Asia Region, which accounted for 33 percent
of incident cases globally. However, the estimated incidence per
capita in sub-Saharan Africa is now nearly twice that of the South-East
Asia Region, approaching 400 cases per 100,000 people.

In the United
States, non-Hispanic blacks accounted for 28 percent of new
TB cases in 2003. They also accounted for the highest percentage
of TB cases in the U.S.-born population--44 percent--and
13 percent of cases among the foreign-born.

"In populations vulnerable to TB, it's exciting to consider the
possibility that innate immunity might be enhanced by a vitamin
costing just pennies a day," says HSPH
Dean Barry Bloom, a study co-author
and the Joan L. and Julius H. Jacobson II Professor of Public Health.

"This study shows how variations in vitamin D synthesis may make some
individuals susceptible to TB," says Bloom. "It also reveals
a new mechanism by which the innate immune response--conserved through
evolution, from fruit flies to mice to humans--battles certain pathogens."

A mystery fathomed
In 1992, a team led by Bloom discovered how macrophages killed
M. tuberculosis in laboratory mice: by producing nitric
oxide. So scientists
began hunting
for a similar mechanism in human immune cells in test tube
studies. They and many
other scientists searched and searched, but the quest proved disappointing.

Then
a breakthrough came, in 2005, in the laboratory of Robert
Modlin, a professor of dermatology and microbiology, immunology, and
molecular
genetics
at UCLA
and a longtime collaborator of Bloom's. In Modlin's lab,
a postdoctoral scholar named Philip Liu and his co-workers began
genetically screening two related
types of human white cells to see which genes were switched "on"
and "off" when the cells encountered M. tuberculosis.
Only in the macrophages capable of killing the tubercle bacillus
did they find that the major switched-on
gene encoded the
receptor molecule for vitamin D.

Suddenly, the researchers were on the
way to uncovering a new mechanism for killing the tubercle bacillus--a
mechanism that bore no resemblance to the one they and others had demonstrated
in mice, and that had been implicated previously
in destroying other microbes.
In the test tube, the research team found that the interaction between
surface molecules on the bacterium and the macrophage triggered a
chain of events
within the immune scavenger cell: a dramatic increase in vitamin
D receptors and production
of an enzyme that converted vitamin D to its active form. Both steps
proved crucial to the genesis of a protein fragment, cathelicidin,
that can destroy
M. tuberculosis,
an otherwise tough, resilient pathogen.

The UCLA-HSPH collaborators
offer a tantalizing explanation for why scientists' hunt
for similar TB-killing mechanisms in mice and men has not panned
out. Humans, who are active by day, may have evolved the ultraviolet-light-and-vitamin-D
pathway
to kill microbes inhaled in small numbers. Mice, being nocturnal
and not exposed in nature to the tubercle bacillus, depend primarily
on a different pathway to
resist pathogens.

Next, the researchers compared the response
to M. tuberculosis of immune cells from blood serum donated
by African Americans and
whites.
After
confirming that the sera from African Americans had lower levels
of vitamin D, they
cultured
macrophages from it and discovered, first, that the cells made
63 percent less cathelicidin than cells cultured from the sera
of white
donors;
and second,
that
these cells were ineffective in killing the TB pathogen. Moreover,
bringing the vitamin D precursor in African American serum up
to
the levels seen
in Caucasian
serum sparked production of microbicidal cathelicidin by the
macrophages.

Bloom says the newfound mechanism may
explain the historic link between TB resistance in humans and sunlight.
Starting in the
late 1800s,
sunlight and
fresh air were
thought to help cure active TB, which led to the great sanatorium
movement. Wheeling patients' beds out onto these institutions'
sunlit porches gave way to effective antibiotics in the mid-20th
century, Bloom says, "but our
research shows that the idea may not have been totally crazy.
It's unfortunate that sanatoria later installed windows, since glass
filters out ultraviolet rays."

If the studies in the laboratory help
explain the increased susceptibility of people in Africa and Asia
to tuberculosis, Bloom says, they
also raise difficult questions about the role of race as
a factor in disease
susceptibility.

"Race is a very vague concept, hard to
define in any scientific way," he says. "From human genetic studies,
it is
clear that there
are greater genetic
differences between any two individuals than between any
classification of races. In the case of skin pigmentation,
it is important
to point out that essentially
all of us have melanin pigment in skin organelles called
melanosomes."
Based on the Science study, Bloom says, "Differences between
Africans, Asians, and European populations that might relate
to susceptibility
to tuberculosis are essentially quantitative--a matter of how much
melanin they make--not
qualitative."

The study's results are currently limited
to the lab, Bloom cautions. But he believes they may be promising enough
to
warrant a clinical trial of vitamin
D supplementation in Africa or Asia. For high-risk populations
in the developing world, he says, the possibility that a simple, inexpensive
vitamin pill might
boost innate resistance to developing TB--one of humankind's
oldest, most resilient foes--is an intriguing idea worth
testing.

Of the world's 22 highest-burden TB countries,
nine are in Africa, according to the World Health Organization (WHO).
They are: Democratic Republic of Congo,
Ethiopia, Kenya, Mozambique, Nigeria, South Africa, Uganda,
United Republic of Tanzania, and Zimbabwe. These countries
face huge challenges related to the HIV/AIDS
epidemic, which greatly weakens the immune system and heightens
the risk of infection and death caused by TB.

The largest
number of new TB cases in 2004 occurred in WHO's 11-country South-East
Asia Region, which accounted for 33
percent of incident cases globally.
However, the estimated incidence per capita in sub-Saharan
Africa is now nearly twice that of the South-East Asia
Region, approaching 400 cases per 100,000 people.

In the United States,
non-Hispanic blacks accounted for 28 percent of new TB cases in 2003.
They also accounted
for
the highest
percentage of TB
cases in
the U.S.-born population--44 percent--and 13 percent
of cases among the foreign-born.

Karin Kiewra is editor of the Review and
associate director of Development Communications.